Marfan's syndrome pathophysiology
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Editors-In-Chief: William James Gibson, C. Michael Gibson, M.S., M.D.
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D.  ; Assistant Editor-In-Chief: Cassandra Abueg, M.P.H. 
Marfan syndrome has been linked to a defect in the FBN1 gene on chromosome 15, which encodes a glycoprotein called fibrillin-1. Fibrillin is essential for the formation of the elastic fibers found in connective tissue, as it provides the scaffolding for tropoelastin. Elastic fibers are found throughout the body but are particularly abundant in the aorta, ligaments and the ciliary zonules of the eye, consequently these areas are among the worst affected. Without the structural support provided by fibrillin many connective tissues are weakened, which can have severe consequences for support and stability.
Marfan syndrome is inherited as a dominant trait. In so far as the pattern of inheritance is dominant, people who have inherit just one affected FBN1 gene from either parent will develop Marfan syndrome. This expression of the syndrome can range from mild to severe.
A related disease has been found in mice, and the study of mouse fibrillin synthesis and secretion, and connective tissue formation, has begun to further our understanding of Marfan syndrome in humans. It has been found that simply reducing the level of normal fibrillin-1 is associated with a Marfan-related disease in mice.
High levels of Transforming growth factor beta (TGFβ) are associated with inflammation and also play an important role in Marfan syndrome. Ordinarily, Fibrillin-1 binds TGFβ and inactivates it. In Marfan syndrome, reduced levels of fibrillin-1 allow activated TGFβ to damage the lungs and heart. Researchers now believe that the inflammatory effects of TGF-β, on the lungs, heart valves, and aorta weaken the connective tissues and cause the features of Marfan syndrome. In so far as angiotensin II receptor blockers (ARBs) reduce TGF-β, these agents have been administered to young Marfan syndrome patients, and the expansion of the aorta was indeed reduced.
A defect in the gene TGFβR2 on chromosome 3, a receptor protein of TGFβ, has also been related to Marfan syndrome. Marfan syndrome can often be confused with Loeys-Dietz syndrome, a similar connective tissue disorder resulting from mutations in the TGFβ receptor genes TGFβR1 and TGFβR2.
Marfan syndrome is an autosomal dominant disorder caused by mutations in the Fibrillin-1 gene encoding an extracellular matrix protein which constitutes an essential component of microfibrils, critical in formation of elastin. Engvall first isolated the protein from human fibroblast cell culture in 1986, demonstrated its function as a component of extracellular microfibrils and its widespread expression through connective tissue in many organ systems . Early linkage studies of families with Marfan syndrome mapped the gene to 15q21.1 , surprising some investigators who suspected defects in the Elastin gene were causal. Subsequent mutational analysis of FBN1 in patients with Marfan system revealed identical missense mutations in two unrelated patients9. Many linkage studies have been performed and demonstrate that most families have private mutations. The FBN1 gene is very large, consisting of 65 exons. It encodes a 350 kiloDalton protein and is highly conserved between different species.
Familial mutations of the FBN1 gene account for 75% of cases of Marfan syndrome and their corresponding phenotype is inherited in a dominant fashion. Over 500 different FBN1 mutations have been detected in Marfan syndrome patients . 56% of these mutations are missense mutations, most often by creating or substituting a cysteine in a cbEGF domain critical for calcium binding . Missense mutations are clustered in loci with cbEGF domains and typically cause moderate to severe phenotype . Other documented mutations include nonsense, frameshift and splice site mutations. Complete deletions of a FBN1 allele are very rare. 90% of FBN1 mutations are private to an individual or family10. The incredibly diverse set of mutations that cause the syndrome suggest that these mutations generally reflect loss-of-function cause a dominant negative phenotype. Haploinsufficiency and other theories have been proposed to account for the dominant negative phenomenon which will be detailed later.
No FBN1 mutation can be identified in 10% of Marfan syndrome patients . In this subset of patients, mutations in the transforming growth factor-beta receptor 2 (TGFBR2) are causal. Families with TGFBR2 mutations display autosomal dominant inheritance with variable penetrance.
How FBN1 and TGFBR2 mutations cause the syndrome is not well understood. Early data suggests that the mechanism of pathogenesis may involve altered calcium binding FBN1 proteins, as suggested by the predominance of mutations in putative calcium binding regions of the FBN1 gene. The gene contains 47 tandemly repeated calcium binding epidermal growth factor-like domains (cbEGF). These domains contain six cysteine residues that are spaced in a conserved fashion and function to both coordinate calcium binding and form disulfide linkages which govern protein folding. Mutations in cbEGF domains make the Fibrillin-1 proteins more vulnerable to proteolytic degradation and cleavage ,.
The dominant negative inheritance of the disorder suggests mechanisms for molecular pathogenesis. Indeed, other diseases of connective tissue have an established pathway of dominant negative pathology such as osteogenesis imperfecta, a disorder caused by defects in the collagen-1 gene. Because collagen assembles from several monomers, a defect in one protein can disrupt the folding and thus function of the entire assembly, a phenomenon called interference. Similarly, microfibrils are composed of several fibrillin monomers and it is suspected that interference may occur in Marfan syndrome. More complex interactions may be at play as well. Many patients show dramatically decreased expression of FBN1, far below a simple halving that would be expected from loss of one allele. Further, patients with a mild phenotype have been identified who express very low levels of the mutant allele.
Conversely, there is a great deal of evidence suggesting that haploinsufficiency of FBN1 causes the disease. In a mouse model, transgenic expression of a missense mutant FBN1 gene which caused vascular hallmarks of disease with only one normal allele did not cause disease in mice with two normal alleles . A second mouse study showed that mice with loss of one FBN1 allele displayed aortic manifestations of the disease, and transgenic expression of a wild-type FBN1 in these same mice was able to rescue the normal phenotype . Finally, a 2010 report of 10 patients with full deletions of one copy of the FBN1 gene showed that seven of these patients fulfilled the Ghent criteria, while the others were quite young at examination but still displayed facial and skeletal manifestations of the disease . Thus, haploinsufficiency can account for the dominant negative effect of mutations in one FBN1 alllele. Various genetic modifiers of expression of the normal FBN1 allele are thought to account for the observed variance in disease severity. Modulating expression of the normal FBN1 gene is therefore an attractive therapeutic target.
Fibrillin-1 defects are thought to manifest in two pathways, abnormal construction of microfibrils directly causing disease and altered cytokine signaling resulting from microfibrilar misregulation of these molecules.
Mouse models have showed that fibrillin-1 is not required for the construction of elastic fibers, instead suggesting that fibrillin-1 is required for the maintenance of elastic fibers. Elastic fibers connect to vascular smooth muscle cells in fibrillin-1 dependent ways. When these connections are disrupted, the smooth muscle cells begin secreting matrix metalloproteinases 2 and 9. Following this misregulation of extacellular matric degrading enzymes, elastic fibre calcification, inflammation and smooth muscle proliferation follow, occasionally causing collapse of the vessel wall. This pathology is not unique to mice, indeed it accurately reflects pathologic changes observed from human specimens. Marfan syndrome thus reflects an inability to maintain structural integrity of the vessel wall rather than an instrinsic inability to create sound vessel architecture and subsequent weakening by mechanical forces.
FBN1 was observed to have a high degree of homology with latent Transforming Growth Factor beta binding proteins. TGF-β is known to be secreted as a complex bound to a latency peptide and a latent TGF-β binding protein which is in turn bound by extracellular matrix. These two observations led investigators to examine the possibility that fibrillin-1 mediates the sequestration of TGF-β molecules in the extracellular matrix. The role of TGF-β is thought to explain the disease phenotype in tissues not composed largely of elastic fibers. This hypothesis has been confirmed in the setting of atrioventricular valve complications with a mouse model showing that increased TGF-β signaling causes myoxamatous degeneration of atrioventricular valves in FBN1 deficient mice. Injecting mice with an anti-TGF-β antibody was sufficient to rescue the normal phenotype with respect to valvular disease .
Increased TGF-β signaling is reflected by higher concentrations of the cytokine in both Marfan syndrome patients (6 fold increase in concentration) and mice with FBN1 mutations. Marfan syndrome mice treated with losartan, an angiotensin II type I blocker which attenuates TGF-β activation, experienced a significant reduction in plasma TGF-β concentration. This finding was also replicated in Marfan Sydrome patients. Promisingly, aortic root diameter was also significantly reduced in mice receiving losartan .
Current efforts aim at identifying molecular events occurring downstream of TGF-β signaling as possible therapeutic targets. TGF-β dependent activation of matrix metalloproteinases 2 and 9 has been implicated in disease pathogenesis. Data from mouse models shows that the matrix metalloproteinase antagonist doxycycline can slow aortic root growth .
The following conditions that can result from having Marfan's syndrome and may also occur in people without any known underlying disorder. what leads doctors to a diagnosis of Marfan syndrome is family history and a combination of major and minor indicators of the disorder that occur in one individual which is a rare manifestation in general population. Example: four skeletal signs with one or more signs in another body system such as ocular and cardiovascular in one individual.
- Aortic aneurysm or dilatation
- Bicuspid aortic valve
- Cystic medial necrosis
- Dural ectasia
- Ectopia lentis
- Flat feet
- Hypermobility of the joints
- Mitral valve prolapse
- Obstructive lung disease
- Pectus carinatum or excavatum
- Retinal detachment
- Sleep apnea
- Stretch marks
- ↑ McKusick V (1991). "The defect in Marfan syndrome". Nature. 352 (6333): 279–81. PMID 1852198.
- ↑ Cotran. Robbins Pathologic Basis of Disease. Philadelphia: W.B Saunders Company. 0-7216-7335-X. Unknown parameter
- ↑ Lygia Pereira; et al. (1999). "Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1". Proceedings of the National Academy of Sciences. 96 (7): 3819-3823.
- ↑ Pyeritz RE (2008). "A small molecule for a large disease". N. Engl. J. Med. 358 (26): 2829–31. doi:10.1056/NEJMe0804008. PMID 18579819. Unknown parameter
- ↑ Entrez Gene (2007). "TGFBR2 transforming growth factor, beta receptor II" (Entrez gene entry). NCBI.
- ↑ "Related Disorders: Loeys-Dietz". National Marfan Foundation.
- ↑ Sakai LY, Keene DR, Engvall E (1986). "Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils". The Journal of Cell Biology. 103 (6 Pt 1): 2499–509. PMC 2114568. PMID 3536967. Retrieved 2010-12-22. Unknown parameter
- ↑ Kainulainen K, Pulkkinen L, Savolainen A, Kaitila I, Peltonen L (1990). "Location on chromosome 15 of the gene defect causing Marfan syndrome". The New England Journal of Medicine. 323 (14): 935–9. doi:10.1056/NEJM199010043231402. PMID 2402262. Retrieved 2010-12-22. Unknown parameter
- ↑ Collod-Béroud G, Béroud C, Ades L, Black C, Boxer M, Brock DJ, Holman KJ, de Paepe A, Francke U, Grau U, Hayward C, Klein HG, Liu W, Nuytinck L, Peltonen L, Alvarez Perez AB, Rantamäki T, Junien C, Boileau C (1998). "Marfan Database (third edition): new mutations and new routines for the software". Nucleic Acids Research. 26 (1): 229–3. PMC 147226. PMID 9399842. Unknown parameter
- ↑ 10.0 10.1 Hilhorst-Hofstee Y, Hamel BC, Verheij JB, Rijlaarsdam ME, Mancini GM, Cobben JM, Giroth C, Ruivenkamp CA, Hansson KB, Timmermans J, Moll HA, Breuning MH, Pals G (2010). "The clinical spectrum of complete FBN1 allele deletions". European Journal of Human Genetics : EJHG. doi:10.1038/ejhg.2010.174. PMID 21063442. Retrieved 2010-12-22. Unknown parameter
- ↑ Dietz HC, McIntosh I, Sakai LY, Corson GM, Chalberg SC, Pyeritz RE, Francomano CA (1993). "Four novel FBN1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome". Genomics. 17 (2): 468–75. doi:10.1006/geno.1993.1349. PMID 8406497. Retrieved 2010-12-22. Unknown parameter
- ↑ Michael J Wright HMC. Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders. In: UptoDate; 2010.
- ↑ Reinhardt DP, Mechling DE, Boswell BA, Keene DR, Sakai LY, Bächinger HP (1997). "Calcium determines the shape of fibrillin". The Journal of Biological Chemistry. 272 (11): 7368–73. PMID 9054436. Retrieved 2010-12-22. Unknown parameter
- ↑ Reinhardt DP, Ono RN, Sakai LY (1997). "Calcium stabilizes fibrillin-1 against proteolytic degradation". The Journal of Biological Chemistry. 272 (2): 1231–6. PMID 8995426. Retrieved 2010-12-22. Unknown parameter
- ↑ Judge DP, Biery NJ, Keene DR, Geubtner J, Myers L, Huso DL, Sakai LY, Dietz HC (2004). "Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome". The Journal of Clinical Investigation. 114 (2): 172–81. doi:10.1172/JCI20641. PMC 449744. PMID 15254584. Retrieved 2010-12-22. Unknown parameter
- ↑ Pereira L, Andrikopoulos K, Tian J, Lee SY, Keene DR, Ono R, Reinhardt DP, Sakai LY, Biery NJ, Bunton T, Dietz HC, Ramirez F (1997). "Targetting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome". Nature Genetics. 17 (2): 218–22. doi:10.1038/ng1097-218. PMID 9326947. Retrieved 2010-12-22. Unknown parameter
- ↑ Ng CM, Cheng A, Myers LA, Martinez-Murillo F, Jie C, Bedja D, Gabrielson KL, Hausladen JM, Mecham RP, Judge DP, Dietz HC (2004). "TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome". The Journal of Clinical Investigation. 114 (11): 1586–92. doi:10.1172/JCI22715. PMC 529498. PMID 15546004. Retrieved 2010-12-22. Unknown parameter
- ↑ Matt P, Schoenhoff F, Habashi J, Holm T, Van Erp C, Loch D, Carlson OD, Griswold BF, Fu Q, De Backer J, Loeys B, Huso DL, McDonnell NB, Van Eyk JE, Dietz HC (2009). "Circulating transforming growth factor-beta in Marfan syndrome". Circulation. 120 (6): 526–32. doi:10.1161/CIRCULATIONAHA.108.841981. PMC 2779568. PMID 19635970. Retrieved 2010-12-22. Unknown parameter
- ↑ Chung AW, Yang HH, Radomski MW, van Breemen C (2008). "Long-term doxycycline is more effective than atenolol to prevent thoracic aortic aneurysm in marfan syndrome through the inhibition of matrix metalloproteinase-2 and -9". Circulation Research. 102 (8): e73–85. doi:10.1161/CIRCRESAHA.108.174367. PMID 18388324. Retrieved 2010-12-22. Unknown parameter